msi-1436 and squalamine

Covering: 1993 to 2021 (mainly 2017-2021)Alzheimer's and Parkinson's diseases are neurodegenerative conditions affecting over 50 million people worldwide. Since these disorders are still largely intractable pharmacologically, discovering effective treatments is of great urgency and importance. These conditions are characteristically associated with the aberrant deposition of proteinaceous aggregates in the brain, and with the formation of metastable intermediates known as protein misfolded oligomers that play a central role in their aetiology. In this Highlight article, we review the evidence at the physicochemical, cellular, animal model and clinical levels on how the natural products squalamine and trodusquemine offer promising opportunities for chronic treatments for these progressive conditions by preventing both the formation of neurotoxic oligomers and their interaction with cell membranes.

Topics: Alzheimer Disease; Animals; Biological Products; Chemistry, Physical; Cholestanes; Cholestanols; Humans; Neurodegenerative Diseases; Spermine

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Topics: Angiogenesis Inhibitors; Anti-Infective Agents; Antineoplastic Agents; Aquatic Organisms; Biological Products; Cholestanes; Cholestanols; Humans; Neuroprotective Agents; Spermine; Steroids; Triterpenes

3,20-Amino- and polyaminosteroid analogues of squalamine and trodusquemine were synthesized involving a stereoselective titanium reductive amination reaction in high chemical yields in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against references and clinical bacterial strains exhibiting minimum inhibitory concentrations of 2.5-40 μg/mL. The mechanism of action of these derivatives was determined using bioluminescence for ATP efflux measurements and fluorescence methods for membrane depolarization assays.

Topics: Anti-Bacterial Agents; Cholestanes; Cholestanols; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Spermine; Structure-Activity Relationship

A series of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine were synthesized and evaluated for their in vitro antimicrobial properties against human pathogens. The activity was highly dependent on the structure of the different compounds involved and the best results were obtained with aminosterol derivatives 4b, 4e, 8b, 8e and 8n exhibiting minimum inhibitory concentrations (MICs) against yeasts, Gram positive and Gram negative bacteria at average concentrations of 3.12-12.5 microM.

Topics: Amines; Anti-Bacterial Agents; Cholestanes; Cholestanols; Microbial Viability; Molecular Structure; Spermine; Sterols; Structure-Activity Relationship

A series of 3-amino and polyaminosterol analogues of squalamine and trodusquemine were synthesized involving a new stereoselective titanium reductive amination reaction in high chemical yields of up to 95% in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Activity was highly dependent on the different compounds' structures involved and best results have been obtained with aminosterol derivatives 4b, 4e and 6i exhibiting activities against yeasts, Gram positive and Gram negative bacteria at average concentrations of 6.25-12.5 microg/mL.

Topics: Amination; Anti-Infective Agents; Bacteria; Cholestanes; Cholestanols; Drug Design; Microbial Sensitivity Tests; Oxidation-Reduction; Polyamines; Sensitivity and Specificity; Spermine; Stereoisomerism; Sterols; Titanium

Aminosterols isolated from the dogfish shark Squalus acanthias are promising therapeutic agents in the treatment of infection and cancer. One of these, MSI-1436, has been shown to possess antimicrobial activity slightly better than squalamine. In this study, a series of analogs of MSI-1436 have been synthesized from stigmasterol. The 7 alpha-hydroxy substituent of MSI-1436 was either omitted or the stereochemistry modified to the 7 beta position. Also, analogs of MSI-1436 with 24-sulfate, 24-amino, and 24-hydroxy substituents were synthesized in order to assess the importance of the side chain functional group on antimicrobial activity. All of the analogs possess significant antimicrobial activity, suggesting that substitution at C7 and C24 of the aminosterols plays a minor role in their antimicrobial potency.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Candida albicans; Cholestanes; Cholestanols; Dogfish; Escherichia coli; Hydroxylation; Magnetic Resonance Spectroscopy; Molecular Structure; Pseudomonas aeruginosa; Spermine; Staphylococcus aureus; Stereoisomerism; Stigmasterol; Structure-Activity Relationship

The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral ventricle (intracerebroventricular [ICV]). Systemic or ICV MSI-1436 administration induced similar patterns of Fos immunoreactivity in the brain, especially the paraventricular hypothalamic nucleus (PVN). This brain region integrates neural signals from hypothalamic and brain stem nuclei and regulates feeding behavior, autonomic function, and neuroendocrine function. Microinjection of MSI-1436 into the PVN potently suppressed feeding and reduced body weight for several days. Unlike caloric restriction, MSI-1436 decreased mRNA levels of agouti-related peptide and neuropeptide Y in the hypothalamus. These findings indicate that MSI-1436 acts in the brain to regulate food intake and energy expenditure, likely through suppression of orexigenic hypothalamic pathways.

Topics: Animals; Anticarcinogenic Agents; Appetite Depressants; Brain; Cerebral Ventricles; Cholestanes; Cholestanols; Energy Intake; Energy Metabolism; Injections, Intraventricular; Mice; Mice, Inbred C57BL; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Reference Values; Spermine; Weight Loss